Esophageal cancer represents the 5th most frequent cancer in males worldwide. Given the poor survival rate, advanced stage of the disease at diagnosis and the increasing frequency of the disease it is increasingly important to understand the molecular mechanisms of initiation of these tumors as well as the genes involved in their metastasis. My research will focus on the catenin family member p120ctn and its ability to modulate tumorigenesis as well as cell migration and invasion in vitro and in vivo. p120ctn defines a family of catenin proteins related to beta-catenin that also bind to E-cadherin and stabilizes E-cadherin at adherens junctions. As a result, expression of E-cadherin and p120ctn appear to be coordinately regulated in many cell lines and it is speculated that this may be another mechanism by which E-cadherin expression may be lost and lead to EMT. Interestingly, p120ctn contains 16 different phosphorylation sites, 8 tyrosine and 8 serine/threonine. What kinases directly phosphorylate these sites and under what stimuli are largely unknown. However, it is clear that EGFR activation can induce phosphorylation of p120ctn at least at Y228. Additionally, many splice forms for p120ctn exist. We hypothesize that the different isoforms and phosphorylation sites of p120ctn may regulate its ability to interact with its binding partners and therefore alter its ability to promote tumorigenesis and metastasis. This hypothesis will be pursued by the following interrelated specific aims. Aim 1: To assess the effects different isoforms and phosphorylation mutants have on motility and invasiveness. Expression of p120ctn will be knocked-down in several esophageal cell lines. Various isoforms and phosphorylation-deficient mutants will be introduced and motility and invasiveness of the mutants will be determined through monolayer assays as well as three-dimensional Matrigel and organotypic culture models. Aim2: To understand the role of p120ctn in tumor initiation and progression. We will overexpress EGFR and knockdown p120ctn expressin in vivo and in vitro. We will monitor these EGFR-overexpressing, p120ctn-deleted mice and cell lines for esophageal tumorigenesis and metastasis. Over 14,000 new cases of esophageal cancer were diagnosed in the United States last year and more than 90% of those diagnosed will die of their disease, primarily from metastatic lesions. The proposed studies will provide novel insights into the biological roles of p120ctn in the development and progression of esophageal cancer. Ultimately, these studies may translate into new diagnostic and therapeutic modalities for this deadly disease.